The present invention relates to equipment and methods used to remove or dispense hyperpolarized gases from containers. The invention is particularly suitable for dispensing sterile or pharmaceutical hyperpolarized gases for Magnetic Resonance Imaging (xe2x80x9cMRIxe2x80x9d) applications.
Conventionally, MRI has been used to produce images by exciting the nuclei of hydrogen molecules (present in water protons) in the human body. However, it has recently been discovered that polarized noble gases can produce improved images of certain areas and regions of the body which have heretofore produced less than satisfactory images in this modality. Polarized Helium-3 (xe2x80x9c3Hexe2x80x9d) and Xenon-129 (xe2x80x9c129Xexe2x80x9d) have been found to be particularly suited for this purpose. Unfortunately, as will be discussed further below, the polarized state of the gases is sensitive to handling and environmental conditions and can potentially rapidly decay from the polarized state.
Hyperpolarizers are used to produce and accumulate polarized noble gases. Hyperpolarizers artificially enhance the polarization of certain noble gas nuclei (such as 129Xe or 3He) over the natural or equilibrium levels, i.e., the Boltzmann polarization. Such an increase is desirable because it enhances and increases the MRI signal intensity, allowing physicians to obtain better images of the substance in the body. See U.S. Pat. No. 5,545,396 to Albert et al., the disclosure of which is hereby incorporated by reference as if recited in full herein.
The hyperpolarized gas is typically produced by spin-exchange with an optically pumped alkali metal. The alkali metal is removed from the hyperpolarized gas prior to introduction into a patient to form a non-toxic and/or sterile composition. Unfortunately, the hyperpolarized state of the gas can deteriorate or decay relatively quickly and therefore must be handled, collected, transported, and stored carefully.
The xe2x80x9cT1xe2x80x9d decay constant associated with the hyperpolarized gas"" longitudinal relaxation time is often used to describe the length of time it takes a gas sample to depolarize in a given situation. The handling of the hyperpolarized gas is critical because of the sensitivity of the hyperpolarized state to environmental and handling factors and the potential for undesirable decay of the gas from its hyperpolarized state prior to the planned end use, i.e., delivery to a patient for imaging. Processing, transporting, and storing the hyperpolarized gasesxe2x80x94as well as delivery of the gas to the patient or end userxe2x80x94can expose the hyperpolarized gases to various relaxation mechanisms such as magnetic gradients, contact-induced relaxation, paramagnetic impurities, and the like.
In the past, rigid containers have been used to transport the hyperpolarized gas from a polarization site to an imaging site such as a hospital. Unfortunately, these conventional transport containers can leave relatively large residual amounts of the gas in the container at the end use point. For example, absent active pumping (which generally introduces unacceptable depolarization to the hyperpolarized gas) an atmosphere of hyperpolarized gas typically remains in the transport vessel, in equilibrium with the ambient air pressure. As such, a larger volume of gas is typically transported to the imaging site to provide the volume desired for clinical use. Unfortunately, the hyperpolarized gas is relatively expensive to produce and this wasted residual gas can disadvantageously escalate the cost of the hyperpolarized product even further. Further, as noted above, conventional pump delivery systems which attempt to extract the gas from the transport container can cause the polarization of the hyperpolarized gas to rapidly decay, thereby limiting the life of the product and providing potentially severe time constraints in which successful clinical imaging can be performed.
Further, bag containers have also been used in the past to administer hyperpolarized gas to a subject via inhalation. Unfortunately, the quantity of gas actually dispensed into the bag can vary. Therefore, it can be problematic, especially when blending hyperpolarized gas with a buffer gas, to provide reliable repeatable concentrations and/or quantities of the inhalable hyperpolarized gas or gas mixtures over a plurality of doses. In addition it may be desirable to use different amounts of gas or gas mixtures as well as different sized dose containers, patient to patient.
For example, it may be beneficial to provide different known concentrations of hyperpolarized gases (25%, 50%, and the like) within a relatively constant overall volume of inhalable gas mixture such as a 1 or 1.5 liter volume (the remainder of the mixture being formed by suitable buffer gases). That is, it is often desirable to have a subject inhale a sufficient quantity of the hyperpolarized gas mixture to either partially or substantially xe2x80x9cfullyxe2x80x9d inflate the lungs. For image calibration and/or regulatory agency guidelines of human or animal administered hyperpolarized gas, it can be desirable to provide reliable doses of predetermined inhalable volumes of the hyperpolarized gas mixture. Unreliable concentrations can, unfortunately, yield varying signal intensities, dose to dose. On the other hand, dispensing only hyperpolarized gas (no buffer gas) can be more costly, and unnecessary from an image viewpoint, as successful images can be obtained with lower concentrations of hyperpolarized gas.
Accordingly, there remains a need to provide improved extraction systems and containers to reduce the depolarizing effect of the extraction system, to relatively efficiently deliver the hyperpolarized gas to the desired subject, and provide more reliable concentrations and/or dosages of hyperpolarized gas.
In view of the foregoing, it is an object of the present invention to provide improved methods to extract hyperpolarized gases from polarization cells or vessels, collection, and transport vessels in a way which reduces the de-polarization of the gas attributed thereto.
It is another object of the invention to reduce the residual amounts of hyperpolarized gas in collection vessels or transport vessels at the end use site.
It is an additional object of the present invention to provide improved gas dispensing and metering methods and systems which allow more reliable dose equantities of hyperpolarized gases and/or concentrations of hyperpolarized gas mixtures to be dispensed.
It is yet another object of the invention to provide improved gas dispensing methods and associated containers and apparatus to reduce any degrading effect that the dispensing may have on the polarized life of a hyperpolarized product so that the hyperpolarized product retains sufficient polarization at the end use site to allow effective imaging at delivery.
It is still another object of the present invention to provide dual purpose transport containers which are configured to both collect and transport the hyperpolarized gas.
It is another object of the present invention to provide improved dose metering of the hyperpolarized gas into containers in a manner which reduces depolarizing activity associated with the dispensing and delivery of the hyperpolarized gas to a subject.
It is yet another object of the invention to provide methods and apparatus which can reduce the de-polarizing effects on the hyperpolarized state of the gas attributed to active dispensing of the gas from a polarization cell, collection, or transport vessel.
It is another object of the present invention to provide improved methods for inhibiting the introduction of oxygen into gas extraction systems or hyperpolarized gas flow paths.
It is an additional object of the present invention to provide a masking method, which inhibits the direct contact of hyperpolarized gas with a potentially de-polarizing material or surface.
It is another object of the present invention to provide a polarization verification method which can identify the expiration date of the hyperpolarized gas externally so that hospital personnel can visually determine the status of the gas prior to delivery to a patient.
These and other objects are satisfied by the present invention which is directed to hyperpolarized gas extraction systems, methods, and associated containers which are configured to remove or extract the hyperpolarized gas from a container and reduce the amount of residual gases unrecovered therefrom in a way which reduces the depolarization of the hyperpolarized gas. In particular, a first aspect of the present invention is directed to a method for extracting a quantity of hyperpolarized noble gas from a container which includes directing a liquid into a container holding a quantity of hyperpolarized gas therein. The liquid contacts the hyperpolarized gas and forces the gas to exit the container separate from the liquid into an exit path operably associated with the container, thereby extracting the hyperpolarized noble gas from the container. In a preferred embodiment, the liquid comprises water which has been sterilized and partially, and more preferably, substantially de-oxygenated and/or deionized.
Another aspect of the present invention is directed towards a method similar to that described above, but this method introduces a quantity of fluid (such as gas or liquid) into the container to push the hyperpolarized gas out of the container. The liquid aspect is similar to that described above.
In one embodiment, wherein the fluid is a gas, the gas is preferably non-toxic and suitable for inhalation by a patient. As such, the extraction gas can mix with the hyperpolarized gas to form a hyperpolarized gas mixture as it exits from the container.
In another embodiment, the hyperpolarized noble gas exits the container separate from the extraction gas. In this embodiment, the extraction gas has a density which is substantially different from the hyperpolarized gas. For example, for 129Xe, the extraction gas is preferably selected so that the hyperpolarized gas has a density which is greater than the extraction gas so that the extraction gas has a density which is less than the hyperpolarized gas. In this embodiment, the exit path is preferably positioned on the bottom portion of the container during the extraction while the extraction gas is introduced into the top portion of the container. This allows the heavier 129Xe to exit out of the bottom of the container while the lighter weight extraction gas remains therein.
In another embodiment, the hyperpolarized gas is 3He, and the extraction gas is preferably selected such that it has a density which is greater than that of 3He. In this embodiment, the exit path is preferably positioned on the top portion of the container while the extraction gas is introduced into the bottom of the container. As such, the lighter 3He exits from the top of the container while the heavier extraction gas remains in the container.
In an additional aspect of the present invention, the extraction method includes engaging a gas transfer source with the container and drawing a quantity of hyperpolarized gas from a container such that the gas is controllably removed therefrom. In a preferred embodiment, the gas transfer source is a syringe that is inserted into the sealed exit path (via an access port) of the container to remove the hyperpolarized gas therefrom. Preferably, the gas transfer source is configured with gas contact surfaces which are friendly to the hyperpolarized state of the gas, i.e., coated with or formed of materials which do not cause excessive depolarization or which inhibit depolarization.
In certain embodiments, a quantity of non-polarized buffer gas into the syringe prior to introducing the hyperpolarized gas therein such that the non-polarized buffer gas is held in the chamber during the hyperpolarized gas introduction therein and the plunger is translated a first distance in the syringe away from the port in response to the quantity of non-polarized gas received therein and second further distance in response to the additional quantity of hyperpolarized gas introduced therein. The syringe can be pre-filled with a quantity of a desired buffer gas such as nitrogen and then filled with the hyperpolarized gas. Together, the plunger of the syringe can force the gases from the syringe chamber into a desired receiving line or container.
Another embodiment of the present invention is directed to methods of preparing a hyperpolarized gas extraction system to inhibit the presence of oxygen therein. The method includes: (a) introducing a quantity of inert noble purge gas into a gas flow path of a gas extraction system; (b) evacuating the flow path of the gas extraction system; (c) repeating the purging and evacuating steps; (d) then introducing additional purge gas into the gas flow path of the extraction system until the pressure therein is at about or above atmospheric pressure so as to inhibit oxygen from entering therein; and (e) subsequently (such as 10 minutes to about 2-4 hours or more later) introducing a desired quantity of hyperpolarized gas in the flow path of the extraction system.
Another aspect of the present invention is directed to a method of masking the potentially depolarizing effects of internal components or surface areas associated with the container. This method includes introducing a quantity of fluid (preferably a liquid) into the container and covering at least one predetermined exposed internal surface of the container with the fluid (liquid) to inhibit direct contact between the internal surface and the hyperpolarized noble gas, thereby masking the exposed surface with a fluid (liquid) to inhibit the depolarization of the gas in the container. In a preferred embodiment, the container is oriented to direct the masking fluid (liquid) into the desired area and the predetermined area includes covering a valve or seal in fluid communication with the container.
Yet another aspect of the invention is directed to a method of decreasing the residual amount of hyperpolarized gas remaining in the container when not using an active pumping or removal system. The method includes introducing a quantity of hyperpolarized noble gas into a small container (preferably less than about 500 cm3, and more preferably less than about 200 cm3) at a pressure of about 3-10 atm. The container is then sealed and transported to a use site remote from the polarization site where the container is opened to release the gas by allowing the container to depressurize to ambient pressure. This is a high pressure, low volume container/method which decreases the amount of residual gas left in low pressure, relatively high volume containers typical of conventional delivery methods/containers. This method is particularly suitable for 3He as higher pressures introduced to the hyperpolarized 3He still yield relatively long T1""s.
An additional aspect of the invention is directed to a method of extracting hyperpolarized gas from a container by positioning a resilient member in fluid communication with the internal chamber of the container holding hyperpolarized noble gas. The resilient member is then expanded to extend into the container and contact the hyperpolarized gas. The gas is forced to exit the container away from the expanded resilient member. Preferably, the resilient member is sealed to the container to prevent the fluid used to expand or inflate the resilient member from contacting the hyperpolarized noble gas. Also, it is preferred that the resilient member be formed from or coated with a material which is friendly to polarization of the gas in the container. Stated differently, a material which is (substantially) not depolarizing to or which inhibits depolarization associated with surface contact with the hyperpolarized gas.
Another aspect of the present invention is directed to improved containers for processing and transporting hyperpolarized gases. In one embodiment, the container comprises a chamber and a quantity of hyperpolarized gas disposed therein. The container includes a resilient member which is positioned to be in communication with the hyperpolarized gas in the chamber. The resilient member has a first collapsed position and a second expanded position. When in the second position, the resilient member extends into the chamber a further distance relative to the first position. Preferably, the resilient member expands and retracts responsive to fluid introduced into an inlet port operably associated with the resilient member. Also, it is preferred that the resilient member is sealed such that it inhibits any expansion fluid from contacting the hyperpolarized gas. In operation, the expansion of the resilient member pushes/forces the hyperpolarized gas to exit the container, thereby actively forcing the hyperpolarized gas out of the container. Advantageously, this configuration can reduce the residual amounts of the gas left in the container while also minimizing potentially depolarizing interactions attributed to the active removal apparatus.
In an alternative embodiment, the container includes a hyperpolarized gas holding chamber and a quantity of hyperpolarized gas disposed therein. The container also includes an access port which is in fluid communication with the holding chamber and which is resiliently configured to receive a portion of a syringe therein. Preferably, the container also includes a valve and an externally accessible connector, such as a lure or septum type connection, which provides an xe2x80x9cair-tightxe2x80x9d seal for drawing the hyperpolarized gas from the container in a manner which reduces the possibility of the introduction of air therewith. Preferably, the syringe plunger and body and septum are formed from or coated with polarization friendly materials. Advantageously, controlled amounts of the gas can be removed from the transport vessel and conveniently be delivered to the patient by simply reversing the plunger to inject or deliver the desired quantity of hyperpolarized gas without complex machinery and the like. Additionally, masking liquid can be used in the container as noted above.
In an additional embodiment, the container comprises a gas holding chamber, a quantity of hyperpolarized gas, and two ports (an inlet port and an outlet port) in fluid communication with the chamber. The inlet and outlet ports are positioned on different sides of the chamber. Preferably, the two ports are radially misaligned and positioned at least 90 degrees apart from the other. It is also preferred that the two ports be offset relative to the other. For example, in one embodiment (during extraction of the gas) the exit port is above the inlet port. Similarly, in another embodiment, the inlet port is above the exit port.
The containers or transport vessels are preferably configured to reduce surface or contact depolarization by forming a contact surface of a material of a thickness which acts to minimize any associated surface or contact depolarization. In addition, the outer layer is preferably configured to define an oxygen shield overlying the inner layer and is configured to minimize the migration of oxygen into the container. Suitable materials and thicknesses and the like are described in U.S. Pat. No. 6,128,918, to Deaton et al., filed Jul. 30, 1998, entitled Containers for Hyperpolarized Gases and Associated Methods. The contents of this patent are hereby incorporated by reference as if recited in full herein. The container material can comprise one or more of a high-purity metal film, high-purity impermeable glass, high-purity metal oxide, and high-purity insulator or semiconductor (for example, high purity silicon).
It is additionally preferred that the container use seals such as O-rings which are substantially free of paramagnetic impurities. The proximate position of the seal with the hyperpolarized gas can make this component a dominant factor in the depolarization of the gas. Accordingly, it is preferred that the seal or O-ring be formed from substantially pure polyethylene or polyolefins such as ethylene, propylene, copolymers and blends thereof Of course, fillers which are friendly to the hyperpolarization can be used (such as substantially pure carbon black and the like). Alternatively, the O-ring or seal can be coated with a surface material such as LDPE or deuterated HDPE or other low-relativity property material or high purity metal.
Another aspect of the present invention is directed towards a method for improving the transfer efficiency of the hyperpolarized gas such as from the polarization cell in the hyperpolarization apparatus. In certain embodiments, the method comprises the steps of positioning a chamber in fluid communication with the polarization cell, directing a quantity of hyperpolarized gas out of the polarization cell and into the chamber, and cooling the chamber to improve the transfer of hyperpolarized gas from the polarization cell. The cooling step can cool the container substantially, such as below the freezing point of water, and more preferably to the temperature of dry ice (195 K), and most preferably to cryogenic temperatures (such as by exposing the chamber to a bath of liquid nitrogen (77 K)). In one embodiment, the hyperpolarized gas is 3He. In another embodiment, the chamber is closed or configured to capture all the gas exiting the polarization cell. The cooling of the chamber can increase the pressures and volumes of gas received into the chamber (and thus out of the polarization cell), improving the transfer efficiency thereby.
Still another aspect of the present invention is a method of identifying the hyperpolarization state of a quantity of hyperpolarized gas (such as at a use-facility or site). The method includes positioning a container having a quantity of hyperpolarized substance in a magnetic field and determining the polarization level of the hyperpolarized substance in the container. An externally visible indicia of polarization, i.e., an identifying mark such as a use-by date is affixed to the container. The identified container is then protected from de-polarizing factors. For example, storing the identified container in a stable magnetic field. Advantageously, this identification can preclude or minimize the delivery of inactive gases to a patient by indicating a shelf life associated with a desired level of polarization of the hyperpolarized substance in the container to hospital personnel. Preferably, the magnetic field has a low field strength, and the determining step includes transmitting a signal to the hyperpolarized substance in the container and receiving a signal back therefrom. The signal back corresponds to the hyperpolarization level of the substance in the container.
Another aspect of the present invention is a method of meting a quantity of hyperpolarized gas into a container. The method includes the step of providing an enclosed sealable gas flow path, the gas flow path extending between a hyperpolarized gas source and a first gas syringe, and between the first gas syringe and a sealable container different from the hyperpolarized gas source. The first gas syringe has a translatable plunger held therein and a port configured to receive gas into and expel gas from the syringe. A quantity of hyperpolarized gas is released in gaseous form from the hyperpolarized gas source such that it flows into the gas flow path. The hyperpolarized gas is directed in the gas flow path into the first syringe and received in gaseous form into the first syringe. The plunger is translated a distance in the first syringe away from the port in response to the quantity of hyperpolarized gas received therein. Subsequently, the plunger is advanced a desired distance in the first syringe toward the port to direct a desired quantity of hyperpolarized gas in gaseous form from the first syringe into the gas flow path and then into the sealable container thereby meting a desired amount of the hyperpolarized gas into the sealable container.
In certain embodiments, a buffer gas can be similarly meted into the sealable container (from a gas syringe). The same syringe as used for the hyperpolarized gas dispensing can be used to dispense or mete the buffer gas. Alternatively, a separate syringe (i.e., a dual syringe system) can be used. In any event, a more reliable predictable quantity of hyperpolarized gas can be meted into the sealable container to provide for more reliable quantities and/or concentrations of the hyperpolarized gas and the buffer gas mixture over conventional procedures.
A related aspect of the present invention is a hyperpolarized gas dose-meting apparatus. The apparatus includes a hyperpolarized gas source, a first valve operably associated with the hyperpolarized gas source and a first gas syringe in fluid communication with the hyperpolarized gas source. The apparatus also includes a first enclosed flow path extending between the hyperpolarized gas source and the first syringe, a second valve operably associated with the first flow path positioned intermediate the hyperpolarized gas source and the first syringe, and at least one receiving container in fluid communication with the first gas syringe. The apparatus additional includes at least one second enclosed flow path extending between the first syringe and the at least one receiving container, at least one third valve operably associated with the receiving container; and at least one release mechanism operably associated with the second flow path positioned in the second flow path upstream of the third valve and the receiving container to allow the receiving container to be released and sequentially replaced with a second receiving container thereat.
In one embodiment, the hyperpolarized gas source is a polarization cell in a polarizer unit. The apparatus can include a second syringe holding a quantity of buffer gas therein, a third enclosed flow path extending between the second syringe and the receiving container, and a fourth valve operably associated with the third enclosed flow path. The first and second gas syringes can be sized to hold from about 0.5-2 liters of gas therein.
The hyperpolarized gas dose-meting apparatus may also include a holding apparatus configured and sized to hold the first and second syringes therein in side by side alignment. The at least one receiving container can be a single (of sequentially filled containers) or a plurality of containers. In one embodiment, the receiving container has collapsible walls.
An additional aspect of the present invention is directed to a hyperpolarized gas dose-meting gas syringe holding apparatus. The syringe holding apparatus/assembly comprises a first gas syringe having a body with a length, a port formed in a first end portion thereof, and a translatable plunger held therein. The syringe and the plunger having hyperpolarized gas-contacting surfaces formed of polarization friendly materials. The syringe includes externally visual indicia along the length thereof allowing a quantitative assessment of the gas volume held therein. The apparatus further includes a holding shell configured and sized to hold at least the first syringe therein. The holding shell has opposing first and second platform portions. The first platform portion includes an aperture formed therein for allowing the plunger to translate therethrough.
In another embodiment, the apparatus also includes a second syringe, and the holding shell is configured to hold the second syringe substantially alongside the first syringe therein. The syringes may be substantially the same size and shape (capable of holding from about 0.5-2 liters or more of gas therein) and the holding shell is configured to hold the first and second syringes in side by side alignment.
For each of the above, a magnetic field generator either comprising an electromagnet or a plurality of discrete permanent magnets can be arranged to provide (surround) the first syringe and/or the hyperpolarized gas flow paths/receiving container with a substantially homogeneous magnetic holding field. An NMR excitation coil can also be used to monitor the polarization level of the polarized gas at desired locations within the extraction system.
The methods and containers of the present invention can improve the relaxation time (i.e., lengthen the T1) of the hyperpolarized gas such as by allowing active dispensing of the gas from a container in a manner which inhibits depolarization of the hyperpolarized gas. The methods and apparatus of the present invention can also allow for more predictable meting of the hyperpolarized gas so as to meet regulatory guidelines and/or provide more reliable concentrations or quantities of hyperpolarized gases/mixture, and, thus, provide suitable in vivo mammalian (preferably human) doses. Further, the active dispensing can reduce the amount of residual gases left in the container at the removal point, thereby improving the delivery efficiency.
The foregoing and other objects and aspects of the present invention are explained in detail herein.